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Opioid Antagonist Could Improve Cancer Survival

August 5, 2016
Methylnaltrexone bromide has been shown to be effective for relieving opioid-induced constipation (OIC) in patients with terminal illnesses—and new research suggests it could improve survival rates, as well.

Interview with Jonathan Moss, MD, PhD

Opioid-induced constipation (OIC) is a major issue for advanced-stage cancer patients taking opioids. Methylnaltrexone bromide (Relistor) has been shown to be an effective treatment for OIC, and new research suggests the drug could lengthen a patient’s survival.

Jonathan Moss, MD, PhD, is a professor of anesthesia and critical care at the University of Chicago and has spent years studying the usefulness of methylnaltrexone. In a recent retrospective review of two previous clinical trials, he and his colleagues presented the first research to associate opioid blockade with increased cancer survival, data that could have significant implications in how doctors understand metastatic cell growth.1

“This all came from a couple of patients I had when the drug was first approved, and they lived much longer than I expected,” Dr. Moss told Practical Pain Management. “When something like that happens, you have to say ‘Why is that the case?’”

Over 80% of patients with terminal illnesses suffer from some form of constipation,2 which happens despite the use of a conventional laxative, leading to reduced opioid use, worsened analgesia, and low quality of life. A charged naltrexone derivative, methylnaltrexone selectively antagonizes peripheral μ-opioid receptors (MOR) without affecting the nervous system, avoiding pitfalls like opioid withdrawal and increase in pain.3 Methylnaltrexone elicits a rapid response from patients—a bowel movement occurs in the first 30 minutes after taking the drug.4 Unlike other opioid antagonists, namely naloxone,5 methylnaltrexone does not cross the blood brain barrier (BBB).

So Dr. Moss and his colleagues began researching more about the drug, however up to this point, they had lacked human clinical data to better understand methylnaltrexone’s effects on cancer survival in patients with advanced illness (AI).

Prolonged Survival

Two randomized, placebo-controlled registration trials were pooled into their retrospective review (Study 302, NCT00401362; Study 4000, NCT00672477), designed to see whether patients given regular doses of methylnaltrexone had improved survival during the trial period.

*Both trials allowed crossover from placebo to methylnaltrexone #Standard FDA-approved dose is 12 mg/0.6 mL subcutaneous injection

The 117 total patients taking methylnaltrexone had a longer median overall survival (OS) rate compared with patients who only took a placebo (n = 56)—76 days vs 26 days, respectively (P<0.001) (Figure 1). Patients who took placebo and then were switched to methylnaltrexone also had a longer median OS compared with those who just stayed on placebo—75 days vs 36 days, respectively (P<0.001). In particular, patients who responded well to the drug had a longer median OS than those who did not, at 118 vs 58 days, respectively (P=0.001) (Figure 2).

Figure 1. For patients treated with methylnaltrexone, median overall survival rates were higher than those treated with placebo (76 days vs 56 days P = 0.033).

Figure 2. Patients that responded to methylnaltrexone showed better survival than patients who did not.

“We initially thought that perhaps it was just patients were having bowel movements and eating better and their gut was working better—that this could have been an explanation for their survival. But clearly, in an equally sick group of patients, there was no difference in that,” Dr. Moss told Practical Pain Management.

There was no difference in OS between methylnaltrexone and placebo groups among the 134 patients suffering from an illness other than cancer. Also, methylnaltrexone and placebo patients were taking the same approximate doses of opioids, omitting another confounder.

Instead, because methylnaltrexone attenuated opioid-mediated MOR signaling, it may have inhibited cancer cell proliferation in the body, Dr. Moss suggested. This may be more conceivable, given the fact that patients taking methylnaltrexone who had a laxative response also showed a significantly lower rate of tumor progression compared to patients taking placebo or patients taking methylnaltrexone who did not experience a laxative response—7.6% vs 25.4% vs 22.0%, respectively (P=0.003).

“Early on, we began to suspect that methylnaltrexone might inhibit cancer growth. After more than a decade in the lab trying to assess how methylnaltrexone affects cancer, we have the first evidence that it can decrease tumor growth and extend survival in patients who respond to the drug.”

Could μ-Opioid Receptors be Treatment Targets for Cancer?

In recent years, a body of literature has begun to suggest a clinical link between opioid usage and reduced cancer survival.

Zylla et al analyzed patients with metastatic prostate cancer and found that high MOR expression and opioid requirement were independently related to inferior progression-free survival and OS survival rates.6 Researchers also have reported that high opioid exposure in patients with advanced lung and prostate cancers had more pain and shorter survival times compared with patients with low exposure to opioids.7

New preclinical and clinical data may suggest MORs are potential treatment targets for cancer progression, and peripheral opioid antagonists like methylnaltrexone could offer the first insights into how inhibition of MORs may have an impact on the clinical progression of cancer.8 According to Dr. Moss, it wasn’t until the FDA approval of opioid antagonists like methylnaltrexone that doctors could observe these clinical effects.

Now, doctors are exploring the notion that endothelial barriers in cells can be disrupted by opioids, causing cellular leakage that may be related to the proliferation and metastasis of existing tumors in the body. “We hypothesized last year in the article we published in Cancer8 on this very subject—that perhaps that leakage may be in fact related to the metastatic potential of tumors, but we cannot yet prove that in humans,” Dr. Moss told Practical Pain Management.

And another question: If methylnaltrexone is given to a patient with less severe cancer and they take the antagonist for a much longer period of time, could survival rates improve even more?

Dr. Moss pointed out that this research should not be seen as an indictment on the use of opioids for managing pain in patients with advanced illness. While it may be a topic of investigation, Dr. Moss stressed opioids should still be considered important tools in managing advanced cancer pain, especially for palliative care.

“It’s very important we don’t scare our patients,” Dr. Moss told Practical Pain Management. “Particularly right now in this political season, there’s a tendency to drive up discussion about the unwanted effects of opioids and things of that nature. But these are real patients with real problems, and if we had absolute certain evidence we would say so,” but without ironclad proof, there should be no change in clinical practice mandated, given the essential analgesia opioid medications provide to patients with advanced illness. “Having practiced for over 35 years, I’m very sensitive to that.”

Dr. Moss receives royalties from the University of Chicago. He also has been a paid consultant for Salix Pharmaceuticals. However, Salix Pharmaceuticals did not sponsor this study. The other study authors reported no conflicts of interest.



Last updated on: August 8, 2016
Continue Reading:
Combating Opioid-Induced Constipation: New and Emerging Therapies

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